JPH0368520A - Use of 5'-dioxy-5'-methythioadenosine, s-adenosylmetyonine and their salts in manufacture of drug compounds for seborrhea and said drug compound - Google Patents

Abstract

PURPOSE: To use 5'-deoxy 5'-methylthioadenosine, etc., for production of pharmaceutical composition for reducing scalp steatorrea and dandruff-like desquamation and pruritus concerning the scalp steatorrea. CONSTITUTION: This therapeutic agent for reducing steatorrea includes 5'- deoxy-5'-methylthioadenosine, S-adenosylmethionine and a salt thereof. The composition applicable as constitutional administration system includes 50-1600mg, preferably 600-1200mg active ingredient, and the composition for topical administration includes 0.2-16wt.%, preferably 2-8wt.% active ingredient with a pharmaceutical additive and vehicle in combination.

Description

DETAILED DESCRIPTION OF THE INVENTION 5'-y'oxy- 5'-methylthioadenosine (MTA), f9-adenosylmethionine (
SAM.) and their pharmaceutically acceptable salts and their pharmaceutical compositions.

Seborrhea (increased sebum production) is a very frequently encountered condition that can be evident on the hairless dermis (greasy looking epidermis) or in areas containing hair.

Additionally, on suppression, seborrhea is accompanied by desquamation of the sebaceous gland disease dandruff ridges, often associated with the sensation J4 and F4 pruritus of the hair body.

The hair becomes shiny, greasy and sticky.

Therapeutic uses of product classes including MTA k and SAMe as antiviral agents, cell growth inhibitors) and tumorigenic and tissue metamorphosis inhibitors include:
Already known, for example British Patent No. 1,555,99
It has been widely described in literature such as No. 1. anti-inflammatory drug, hypopyretic drug, plateletant
lagregant) and the therapeutic use of these products as sleep-inducing substances is also disclosed in U.S. Patent No. 4.454.
, No. 122 and No. 4,373,097. See the aforementioned patents for a description of methods for making MTA k and SAMe.

There is currently no evidence confirming the ability of MTA or SAMe to reduce seborrhea. In fact, MT
The pharmacological activity of A has not been proven in the field of dermatology, and clinical studies conducted on depressed patients (Mantero M, (2003) and Nozostrino P,
(Pa5torino P, ) 1976) was incidentally observed in SAMs. In fact, the two depressed patients in this study also had psoriasis and showed signs of cutaneous syntomatology (euta) following treatment with parenteral SAMs.
showed a sharp regression of neous ayntomatology). However, this therapeutic effect on the skin disease characteristic of psoriasis was not confirmed for the known antidepressant activity but for the possible 8AMe activity in the dermatological field.

In fact, psoriasis is known to be ascribed to a psychosomatic etiology in some subjects.

Regarding the symptoms of itching, several clinical studies have investigated the effects of SAMs on women suffering from cholestasis during pregnancy (
F'rezza M, et al., 1984
Year; Gomez M, L, (Gomez M, L, )
et al., 1987) demonstrated the ability of the molecule to alleviate symptoms that appeared to be associated solely with abnormal bile outflow. Therefore, the anti-itch effect of SAMs must be attributed to their cholestatic activity. In conclusion, these three
Ai studies have not been linked to the use of 5'-deoxy-5'-methylthioadenosine, S-adenoflumethionine p, and their salts in pharmacological formulations for seborrhea, which is characterized by skin overproduction. Not [Fitz/4'
Trick T., B., and Pernhard J.

D. Fundamentals of structure and diagnosis of skin lesions (Fitz A'to I
JtsukuT, B, )Z(CE:/A,Z,,Uo #7
K, 7! /-Dopague 1. M. to Austen, F.
, ed. Pharmacology of General Drugs, McGraw-Hill Publishing, 1987.
(Fitzpatrik T, B, &
B*rnhard J, D, The 5truc
tureof 5kln 1eslons and f
Undamsntal of diBnoais.

In: Dsrmatology 1n Gener
al Msdlclns, Editedby Fi
tzpatrik T, B, , Eisen A,
Z, , Wolff K, .

Freedberg 1. M, , Au@ten
K, F; McGraw-Hll IBook
Company, 1987. p, 45)) s t,
It cannot necessarily be correlated with a type of itching whose occurrence does not depend on the state of abnormal bile outflow and the state of the liver.

However, the scalp activity of MTA and SAMs in reducing seborrhea and its associated dandruff-like scaling and pruritus has not been described previously.

Many substances have been currently used in the treatment of seborrhea and its associated manifestations (dandruff, pruritus), but most of them have been found to have low therapeutic efficacy. . The compositions that have proven the most effective are low-potency glucocorticosteroids, but these compositions do not have the potential to appear during prolonged steroid therapy. It is clearly difficult to manage because of its unpleasant side effects (eg, if-like rash, skin atrophy).

The purpose of the present invention is to avoid inducing negative side effects.
M for the manufacture of a pharmaceutical composition that substantially reduces scalp N-rhea and its associated dandruff-like scaling and Tt pruritus
The present invention relates to uses of TA, SAMs k and their salts and to pharmaceutical compositions thereof.

In this regard, a pharmaceutical composition comprising MTA, SAMe or a salt thereof as an active ingredient according to the present invention is effective in reducing scalp seborrhea and the dandruff-like scaling and itchiness associated therewith. The present inventors surprisingly discovered this.

This pharmacological activity, which would not be expected based on the known pharmacological activity of these products, has been confirmed by a number of clinical trials; The results obtained are reported below to illustrate the objects and advantages of the present invention.

Clinical Trial 1 Fifty subjects suffering from scalp seborrhea and dandruff-like scaling participated in this clinical trial.

Participants aged 21 to 35 were divided into two balanced groups in a double-blind randomized design.
Treatment was performed for one month with a placebo or MTA administered orally at a dose of 600 x 7 days according to the andomizatlon scheme.

The effectiveness of treatment for seborrhea was evaluated as follows: 0 A lipometer to measure the amount of sebum present in the scalp (
sebomster ) (Model 5M810 College &
Kuhazaka, = + Ron, Nishi a (mod, 8M810
Courage & Khazaka, Colog
ne, Wheat G@rmany)).

Visual comparison to quantitatively understand the following parameters: stickiness of hair and scalp fat, dandruff, and itching.

A fat meter is a device that measures the amount of sebum present on the skin surface, and is based on the principle that the clearer the opaque window of the device, the greater the amount of fat-like substance applied (
Schäfer and Ku/Bushiis Archi
and Kuhn Busglsln Arkiv
fur K11nisehe und Experim
antelleDermatology 238+4
29.1970)).

The device sensor has a thickness of 0. l vx strips of opaque glass material (in place of opaque windows)
Contains. Area e4st? Underneath that part of the strap during use is a mirror that projects with the strap by about 1 x m from the sensor. A spring is connected to the mirror to apply constant pressure to that area of the skin being examined. The Strino surface, pressed in this way against the skin surface for 30 seconds, becomes more transparent due to the absorption of sebum. The transparency of the window is measured photometrically, increasing linearly with increasing amount of sebum absorbed. Sebum level (ge
bometrle value ) is milligram/c! according to the conversion table using the following formula. It can be converted to IL2.

(Here, vS = sebum value, 6 = base of natural logarithm = 2.71
8) Oral administration of MTA to sebum turbidity evaluated by fat meter
The effect of treatment with is shown diagrammatically in FIG. In Figure 1, the vertical axis on a scale of 0 to 30 (12) is the average sebum value before treatment (F!A lower histogram) and the average sebum value one month later for subjects treated with MTA or placebo. value('#
The histogram is shown below. The asterisk (*) indicates a significant difference of p(0,05) for the pace value. Statistical analysis was performed using split variance (5plit-plot
variance).

Comparisons between groups and times are made using the Tukey test.
est).

From FIG. 1, it can be seen that there was a significant reduction in scalp seborrhea after oral treatment with 1MTA, indicating that the placebo was ineffective.

The degree of the presence of hair and scalp fat, dandruff and Tl pruritus,
0 to 122) quantitatively indicated on a comparative scale (0 indicates no symptoms, 12 indicates maximum). Before treatment (brighter histogram) and after treatment (brighter histogram) for these three parameters for the group of patients treated with MTA > and placebo.
! The average value of the smaller histogram) is calculated using the average value S D
(meanil″sD ) in Figures 2.3 and 4, respectively; the asterisk (*) indicates p relative to the pace value.
<o, indicating a significant difference in os. Statistical analysis was performed by split variance; comparisons between 0 groups and time were performed by Tachy test.

For each of these three parameters, there is a clear and significant improvement after oral treatment with MTA.

MTA > and different doses of SAMa, i.e. M
TA 50 In9 (10 patients), MTA l
00ri (10 patients), MTA 200■ (10
patients), MTA 400 m9 (10 patients),
MTIA800In9 (10 patients), MTA l
2ooIky (10 patients), MTA 1600In
9 (10 patients), SAMs 50 h; I (
10 patients), SAMe 10 (21N; I (10
patients), 8 M@200W (10 patients),
SAMs 400 m9 (10 patients), SAMs
800 m9 (10 patients), SAMs l 20
(21119 (10 patients) p and SAMe 16
Similar tests were conducted using oral pharmaceutical compositions according to the invention containing 00η (10 patients), and it was found that pharmaceutical compositions containing these doses of the active ingredient also showed a significant improvement in the f parameter. It was found that it shows.

Clinical Trial 2 Patients 19-33 suffering from scalp seborrhea and dandruff-like scaling
Fifty subjects aged 50 years participated in this clinical trial. The subjects were divided into two equal groups according to a double-tone randomization design to receive either a placebo or a topical Rosh containing MTA. The patient was treated with a drug for one month.

Patients were to apply Roshi's topical dressing or wound twice a day. During the clinical trial, patients were allowed to wash their hair once a week with the same premium shampoo in all cases.

The effectiveness of the treatment to reduce sebum turbidity was evaluated using a fat measuring meter (20) to measure the amount of sebum present in the scalp.
Model SM 810 College & Kuhadeka, Colon, West Pl
+).

Visual comparison double to quantitatively know the following parameters: stickiness of scalp fat, dandruff, and pruritus.

The effect of treatment with topically administered MTA on sebum was evaluated using a lipometer and is shown schematically in Figure 5. In Figure 5, the vertical axis of the 0 to 30 (12) scale is the average sebum value before treatment (bright histogram) and the average sebum value one month later (dark histogram) for subjects treated with MTAt or placebo. histogram). Asterisks indicate significant differences of p(0,05) from the base value. Statistical analysis was performed by split variance. Comparisons between groups p and time were performed by Tachy test.

From Figure 5, it can be seen that there was a significant reduction in scalp seborrhea after topical treatment with MTA, indicating that the placebo was ineffective.

The degree of the presence of fat in the hair and scalp, dandruff and itching are determined by O
~122) Quantitatively indicated on a comparative scale (0 indicates no symptoms, 12 indicates maximum). The pre-treatment (lighter histograms) and post-treatment (darker histograms) mean values for these three parameters for the groups of patients treated with MTA h and placebo were defined as mean values with mean SD of fi 6.7 and Shown in Figure 8: Stars indicate p<0. This shows a clear difference in OS. Statistical analysis was performed by split variance. Comparisons between groups and times were made by the Tachy test.

For each of these three parameters, the MTA
After topical treatment with , there is a clear and significant identifiability.

Different doses of MTA k and SAM@ (active ingredient content is shown as in% of Roshi M/drug), i.e. M
TA 0.1% (10 patients), MTA 1% (10
patients), MTA 2% (10 patients), MTA
3% (10 patients), MTA 4% (10 patients)
, MTA 5% (10 patients), SAMs Q, 4
% (10 patients), SAMs 62% (10 patients), SAMs 4% (10 patients) and SAMe
Similar tests were carried out using topical pharmaceutical compositions according to the invention containing 8% (10 patients), and it was found that pharmaceutical compositions containing these doses of the active ingredient also showed a significant increase in this parameter. It was found that there was an improvement.

As a result, the pharmaceutical composition according to the invention, which is suitable for both systemic and local administration, can reduce scalp sebum turbidity and its associated dandruff-like flaking, fat stickiness, without inducing any negative side effects. It was also shown that pruritus can be significantly reduced.

Furthermore, the pharmaceutical compositions obtained containing MTA i or SAMs t or their salts according to the present invention have virtually no acute toxicity when administered orally and can be administered at therapeutic doses in any form of administration. It should also be noted that there is virtually no toxicity.

Compositions containing MTA according to the invention and suitable for systemic administration contain an active ingredient of between 50 and 1600 Da, preferably 60 Da.
0 to 1200% by weight, whereas compositions suitable for topical administration contain the active ingredient in an amount of 0.1 to 5 t% by weight, preferably 0.
．． It can be included in amounts of 25-2% by weight in combination with commonly used pharmaceutical additives and excipients.

Compositions containing SAM according to the invention and suitable for systemic administration contain the active ingredient in an amount of 50 to 1600 μl, preferably 600 μl.
00 to 1200/9, while compositions suitable for topical administration contain the active ingredient in an amount of 0.2 to 16% by weight, preferably 2 to 8% by weight, of a commonly used pharmaceutical grade. may be included in combination with other additives and excipients.

Some non-limiting examples of pharmaceutical compositions according to the invention are given below.

Example 1 Tablets containing MTA 50 tablets (1ffi contains: MTA@rR salt 58.2/
Q (equivalent to 50rn9 MTA) Fine quality cellulose 37.8 m9 Grese ditinated starch 151.2 da Precipitated silica o, 3 mg I stearate/magnesium acid 2.59 Example 2 Tablets containing MTA I OOη One tablet contains: : MTA 7 x Co/l/Bate 15
9.31n9 (equivalent to MTA 100W) Fine quality cellulose 160.0■ Lactulose 100 mesh, 78.2■ Sedimentation wrinkle strength 0.59 Magnesium stearate 2.0W Example 3 MTA20 (controlled release containing 21W)
led-release) tablet release time = 2 hours 1 tablet contains: MTA (citrate 329°3■
(equivalent to MTA of 200 da) Dibasic calcium phosphate dihydrate 48.2
19 Lactulose lOO mesh lo, 0.
09 Hydroxypropyl methylcellulose 20
．． (21r9 Magnesium Stearate
2.5W Example 4 MTA 400'! Modified release tablet release time including =
One 2-hour tablet contains: MTAI, 4-butane disulfonate (equivalent to MTA400r119) Fine quality cellulose dibasic j! Calcium II acid trihydrate carboxyvinyl polymer glyceryl behenate Example 5 Satuchet containing MTA 800 ■ One satuche containing two MTA p-Toluenesulfonate (equivalent to MTA 800 ■) Fructose Lactose 100 mesh Precipitated silica as/yal Tame Flavor 546. No. 9 150.0■ 118.2In9 25.0 Noda 10.0rikg 1263.31n9 1167.7IOA9 500.0In9 6.0ri 10.09 50, O-hydrogenated vegetable oil 3.0w Example 6 SAMs 200 ”9 Includes gastro register stand F
e-agent (gamtroresistant table)
) One tablet contains: SAMa sulfate p-toluenesulfonate
384 η (SAMs io: /20 (equivalent to 21n9)
77 = -)
150
#Precipitated silica 1 (21
n9 Magnesium Stearate 6η Cellulose Acetophthalate 151n9 Notechnyl Phthalate 5m9 Example 7 GastroResistand Tablets Containing SAMs 400η One tablet contains: SAMel, 4-but/disulphonate 759.2m9
(SAMs ion 40 (equivalent to 21V) precipitated silica
lo, oI71 & fine quality cellulose 125.8 #19 Magnesium stearate 5.0η cellulose acetophthalate) 26.2rn9 diethyl phthalate) 8.81! Example 8 Injectable Form I Bottle Containing SAM 200η Contains: SAMs Sulfate p-Toluene Sulfonate 384
■(equivalent to SAMs ion 200q) Mannit 20 (21n9
L-Lishi 7 300 m9 Sodium Hydroxide 99 Add water for a total volume of 5 m/ for injectable formulation Example 9 Injectable form l bottle containing SAMs 400 'n9 contains: SAM@1, 4-butanedisulfone) 759
．． 2Iv (equivalent to SAMs ion 40016)) L-Licy 232.0m9 Sodium hydroxide 9.69 Add water to total volume of 51 nl for injectable formulation Modified release injection containing SAMs 400m9 Possible forms bottles include: SAMel, 4-butanedisulfone) 75
9.21n9 (equivalent to SAMs ion 400W) Polyethylene L/7 Gri:=Y-L 6000 100.
0In9 hydroxyethyl cellulose lo,
0"+9L-'J'/n
3
23,0m9 Sodium hydroxide
9.6 Add water to make the total volume 5 for injectable formulations! :
Example 11 Modified Release Injectable Form 1 Containing MTA200''9
The bottle contains: MTA 20 (21
n9 polysorbe) 80 10
m9 polyethylene glycol 600 100
Addition of Water to Total Volume for η Injectable Formulation Example 12 Modified Release Suppositories Containing MTA 400m9 One Suppository Contains: MTA Hydroxyglobil Methyl Cellulose Semi-Synthetic Glyceride Example 13 MTA One transdermal system containing 600 Da contains: MTA 1 , 4-butane disulfonate (MTA60
Example 14 Transdermal system containing SAMe 600TII9) Glycerine polyvinyl alcohol polyvinyl pyrrolide/purified water One system contains: SAMe, 4-butane disulfone (equivalent to SAM@ion 600η) Fluid silicone Precipitated silica 400 η 0m9 2530 da 820.2wa], 400.0m9 350.0■ 175.07n9 1575.0m9 1138.8■ 865.7■ 75.2η Example 15 Low silane agent 10 containing 0.25% MTA ( 21 g contains: MTA sulfonate (equivalent to MTA 0.25,9) Methyl p-hydroxype/zoategropyl p-hydroxybenzoate Add purified water to bring the total amount to 10 (21 t) Example 16 MTA 0.5% The low silane agent 10Qm contains: 0.29.9 0.15N 0.05.!i' MTA 1 ,4-butane disulfonate (MTAo,
Example 17 0.68.F 0, l 5.9 0.05.9 MTA 1 Low silane agent 10 containing % Q, d contains: MTA < citrate (equivalent to MTA I II) 1.65# Methyl p-hydroxybenzoate glopyru p-hydroxybenzoate Add purified water to bring the total amount to 100 d Example 18 Spray vinegar solution containing 0.5% MTA 10 (211 Ll) containing: MTAl, 4-butane disulfonate (corresponds to MTA 0.5, P) Glycerol ethyl alcohol methyl p-phenoxybenzoate propyl Add p-hydroxybenzoate purified water to make a total volume of 100 m Example 19 One bottle of low silane agent containing 8% SAMe contains: SAMs sulfate p-toluenesulfonate (SAMe)
Ms ion 200Tn9 equivalent) methyl p-hydroxype/shade n! Add ice cubes to make the total amount 2.5-0, 15. ! i
' 0.05,9 0.68g 1, OO# 5.00.9 0.15. ! i' 0.05. P 384.0 ■ 1.6 η Example 20 A l bottle of low silane agent containing 8% SAMs contains: SAMa 1,4-butanedis/l/bonate
379.61n9 (SAM@ion 20 (equivalent to 21n9) methyl p-hydroxybenzony)
Add 1.6m9rIIm water to make a total volume of 2.5d.

[Brief explanation of drawings]

FIG. 1 shows the effect of treatment with orally administered MTA on sebaceous syndrome as assessed by a lipometer. Figures 2, 3 and 4 show the pre-treatment (
The average values of brighter histogram) and after treatment (II brighter histogram) are shown as mean±SD. FIG. 5 shows the effect of treating sebaceous disease with locally administered MTA as evaluated using a lipometer. Figures 6, 7 and 8 show the mean values before treatment (lighter histograms) and after treatment (darker histograms) for the three parameters for the groups of patients treated with MTA and placebo, respectively, as mean ± SD. This is an indication. Engraving of the drawings Figure 1 MTA Placebo Figure 3 TA Placebo Figure TA Placebo Figure TA Placebo Figure TA Placebo Figure 8 MTA Placebo Procedure Nefu Official Text (Method) % Formula % 1. Case Indication Patent Application Hei 2 -6 (2126 No. 2, Title of the Invention) Use of 5°-deoxy-5°-methylthioadenosine, S-adenosylmethionine and salts thereof in the manufacture of a pharmaceutical composition for reducing sebum turbidity and said pharmaceutical composition 3. Relationship with the case of the person making the amendment Patent applicant name Bio-Research SpA Address 40 Mori Building, 40 Toranomon, 5-13-1 Toranomon, Minato-ku, Tokyo. ) % Formula % 1. Indication of Case Patent Application No. 2126 No. 2, Name of Invention 5°-deoxy-5′-methylthioadenosine, S-adenosine in the manufacture of a pharmaceutical composition for reducing sebum turbidity Use of silmethionine and their salts and the relevant pharmaceutical compositions 3; Relationship with the case of the person making the amendment Patent applicant name Bio-Research SpA 4, attorney June 26, 1990 6, drawings subject to amendment (all drawings) )

Claims (23)

[Claims] (1) 5'-deoxy-5'-methylthioadenosine in the manufacture of a pharmaceutical composition capable of reducing scalp seborrhea and its associated dandruff-like scaling and pruritus;
Uses of S-adenosylmethionine and their pharmaceutically acceptable salts. (2) The use according to claim 1, wherein the pharmaceutical composition is suitable for oral administration. (3) The use according to claim 1, wherein the pharmaceutical composition is suitable for parenteral administration. (4) The use according to claim 2, wherein the amount of the active ingredient used is 50 to 1600 mg. (5) The amount of active ingredient used is preferably 600 to 1200
The use according to claim 4 in mg. (6) The use according to claim 1, wherein the pharmaceutical composition is suitable for topical application. (7) When the active ingredient is 5'-deoxy-5'-methylthioadenosine, the amount is 0.1 to 0.5% by weight of the solution, and when the active ingredient is S-adenosylmethionine, it is 0.2 to 1% by weight of the solution.
Use according to claim 6, used in an amount of 6% by weight. (8) When the active ingredient is 5'-deoxy-5'-methylthioadenosine, the amount is preferably 0.25 to 2% by weight of the solution, and when the active ingredient is S-adenosylmethionine, it is preferably 2 to 8% by weight of the solution. Use according to claim 7, used in amounts of % by weight. (9) Scalp seborrhea and related dandruff characterized by containing 5'-deoxy-5'-methylthioadenosine, 5-adenosylmethionine, or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition capable of reducing desquamation and pruritus. (10) The pharmaceutical composition according to claim 9, which is suitable for oral administration. (11) The pharmaceutical composition according to claim 9, which is suitable for parenteral administration. (12) The pharmaceutical composition according to claims 10 and 11, wherein the active ingredient content is 50 to 1600 mg. (13) Active ingredient content is preferably 600 to 1200
The pharmaceutical composition according to claim 12, which is mg. (14) The pharmaceutical composition according to claim 9, which is suitable for topical administration. (15) When the active ingredient content is 5'-oxy-5'-methylthioadenosine, S
-A pharmaceutical composition according to claim 14, in which the amount of adenosylmethionine is from 0.2 to 16% by weight of the solution. (16) When the active ingredient content is 5'-deoxy-5'-methylthioadenosine, it is preferably 0.25 to 0.25 of the solution.
16. A pharmaceutical composition according to claim 15, wherein the amount is 2% by weight, and in the case of S-adenosylmethionine, preferably from 2 to 8% by weight of the solution. (17) Scalp seborrhea characterized by administering a pharmaceutical composition containing 5'-deoxy-5'-methylthioadenosine, S-adenosylmethionine, or a pharmaceutically acceptable salt thereof as an active ingredient. and treatments that reduce dandruff-like scaling and pruritus associated therewith. (18) The method of treatment according to claim 17, wherein the administration is oral or parenteral. (19) The treatment method according to claim 18, wherein the amount of the active ingredient is 50 to 1600 mg. (20) The amount of active ingredient is preferably 600 to 1200 m
The treatment method according to claim 19, which is g. (21) The treatment method according to claim 17, wherein the administration is local. (22) When the active ingredient content is 5'-deoxy-5'-methylthioadenosine, it is 0.1 to 5% by weight of the solution,
For S-adenosylmethionine, 0.2-16 of the solution
22. The method of claim 21, which is % by weight. (23) When the active ingredient content is 5'-deoxy-5'-methylthioadenosine, it is preferably 0.25 to 0.25 of the solution.
23. The method of claim 22, wherein the amount is 2% by weight, and in the case of S-adenosylmethionine, preferably 2 to 8% by weight of the solution.